Thioureylene liquid compositions

ABSTRACT

The present invention relates to novel liquid compositions and formulations containing a thioureylene compound, a polysaccharide and a liquid vehicle. The compositions and formulations of the invention are useful for dealing with diseases and conditions associated with abnormally high thyroid hormone levels in mammals, such as humans and cats.

TECHNICAL FIELD

The present invention relates to novel liquid compositions containingthioureylene compounds, pharmaceutical formulations based on saidcompositions and their use for lowering thyroid hormone levels inmammals.

BACKGROUND ART

The thyroid hormones thyroxine (T₄) and triiodothyronine (T₃) play asignificant role in the growth, development and differentiation ofnormal cells. The production of T₄ and T₃ is controlled by thethyroid-stimulating hormone (TSH), which is secreted by the hypophysis.An excess of circulating free T₄ and T₃, or both, is associated with thedevelopment of hyperthyroidism (e.g. Grave's disease).

Hyperthyroidism is a relatively common endocrine disorder in mammalsand, particularly, in humans and cats. Typical hyperthyroidismtreatments include chronic administration of an anti-thyroid medication,surgical removal of the thyroid glands or radioactive iodine therapy.These treatments have their limitations and side effects. For instance,anti-thyroid drugs may be difficult to administer orally, especially ifthey are in solid form. On the other hand, surgery is an expensiveoption and may be contraindicated in some cases for older subjects thatcould suffer from other diseases as well. Finally, radioactive iodinetherapy may be administered in licensed facilities only and couldrequire patienthospitalization.

Thioureylenes are anti-thyroid compounds used widely in the treatment ofhyperthyroidism. This group of drugs includes carbimazole, methimazole,methylthiouracil and propylthiouracil. Se Ginsberg J, et al., CMAJ 2003;4, 168(5):575-585. Thioureylenes act by inhibiting the enzymethyroperoxidase, which mediates the synthesis of T₄ and T₃.

At present, only thioureylene solid formulations have been approved forthe treatment of hyperthyroidism in mammals. However, there is a need inthe art for alternative thioureylene formulations that could improve orfacilitate the treatment of this condition in patients.

DESCRIPTION OF THE FIGURES

FIG. 1 shows the mean plasma levels of methimazole in cats in periods Iand II following the oral administration of a formulation according tothe present invention and the reference product tablets at a dose rateof 5 mg methimazole per subject.

SUMMARY OF THE INVENTION

The present invention relates to novel liquid compositions andformulations comprising a thioureylene compound, a polysaccharide and aliquid vehicle. The compositions and formulations of the invention areuseful for managing diseases and conditions associated with abnormallyhigh thyroid hormone levels, such as hyperthyroidism. Even though thecompositions and formulations of the invention are in liquid form, theyare surprisingly, stable. They also exhibit a pharmacokinetic profileindistinguishable from other solid thioureylene formulations alreadyapproved for human and animal health. At present, there are no stableliquid thioureylene formulations authorized for human or animal use.

The liquid nature of the compositions and formulations of the inventionconfer them a significant advantage, as they are easier to administerthan comparable solid forms. This last trait makes the compositions andformulations of the invention particularly useful for treating mammalsand, especially, humans and cats.

Therefore, in a first aspect, the present invention is directed to acomposition comprising:

-   -   i) about 0.25% to about 1% w/v of a thioureylene compound, a        pharmaceutically acceptable salt, solvate, prodrug or        combination thereof,    -   ii) at least about 0.2% w/v of a polysaccharide, and    -   iii) a liquid vehicle.

Said composition is characterized specifically for being an stableliquid form.

In a second aspect, the present invention relates to processes of makingthe liquid compositions according to the first aspect of the invention.

In a third aspect, the present invention relates to a pharmaceuticalformulation comprising the liquid composition according to the firstaspect of the invention and at least one excipient.

In a fourth aspect, the present invention refers to a liquid compositionaccording to the first aspect of the invention or a pharmaceuticalformulation according to the third aspect of the invention for its useas a medicament.

In a fifth aspect, the present invention is directed to liquidcomposition according to the first aspect of the invention or apharmaceutical formulation according to the third aspect of theinvention for its use in the treatment or prevention of a disease orcondition due to increased thyroid hormone levels. Alternatively, thepresent invention relates to the use of a liquid composition accordingto the first aspect of the invention in the manufacture of a medicamentfor the treatment or prevention of a disease or condition associatedwith increased thyroid hormone levels.

In a sixth aspect, the present invention relates to a method forreducing the thyroid hormone levels in a subject, which comprisesadministering to the subject a therapeutically effective amount of theliquid composition according to the first aspect of the invention or apharmaceutical formulation according to the third aspect of theinvention.

DESCRIPTION OF THE EMBODIMENTS 1. Definitions

The term “carbimazole”, as used herein, refers to ethyl3-methyl-2-sulfanylidene-imidazole-1-carboxylate, CAS [22232-54-8], acompound of molecular formula C₇H₁₀N₂O₂S and structural formula:

Carbimazole is a methimazole prodrug. After its administration andabsorption, carbimazole is converted to methimazole in vivo.

The term “excipient” as used herein, means any component, other than theactive substance(s) intentionally added to the formulation of a dosageform. Exemplary excipients are disintegrants, lubricants, plasticizers,binders, fillers, colorants, flavor masking agents, flavoring agents,stabilizers, foaming agents, sweeteners, pore-forming agents, acids(e.g. citric acid, tartaric acid), sodium chloride, a bicarbonate (e.g.sodium, potassium), sugars and alcohols. Some excipients can servemultiple purposes (e.g. filler and disintegrant). See EuropeanPharmacopoeia 8.0.

The term “methimazole”, as used herein, refers to1-methylimidazole-2-thiol, CAS [60-56-0], a compound of molecularformula C₄H₆N₂S and structural formula:

The term “methylthiouracil”, as used herein, refers to6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one, CAS [56-04-2], acompound of molecular formula C₅H₆N₂OS and structural formula:

The term “Ph. Eur. 2.2.3.” as used herein, refers to the “PotentiometricDetermination of pH” measurement protocol [European Pharmacopeia 8.0,January 2008: 20203, February 2014].

The term “polysaccharide”, as used herein, refers to a complexcarbohydrate composed of a chain of monosaccharides joined together byglycosidic bonds.

The term “polyvinylpyrrolidone”, as used herein, refers to1-ethenylpyrrolidin-2-one, CAS [9003-39-8], a compound of molecularformula (C₆H₉NO)_(n), also known as PVP or povidone.

The terms “prevent”, “preventing” and “prevention” as used herein, referto inhibiting the inception, or decreasing the occurrence or recurrence,of a disease in a subject. Prevention may be complete (e.g. the totalabsence of pathological cells in a subject) or partial. Prevention alsorefers to a reduced susceptibility to a clinical condition.

The term “propylthiouracil”, as used herein, refers to6-propyl-2-sulfanylpyrimidin-4-one, CAS [51-52-5], a compound ofmolecular formula C₇H₁₀N₂OS and structural formula:

The term “subject” as used herein, refers to a mammalian, such as ahuman being, a non-human primate (e.g. chimpanzees, apes, monkeyspecies), a farm animal (e.g. cattle, sheep, pigs, goats, horses), adomestic mammal (e.g. dogs, cats) or a laboratory animal (e.g. mice,rats, guinea pigs). The term does not denote any particular age or sex.

The term “therapeutically effective amount” as used herein, refers toany amount of a compound, composition or formulation which, whenadministered to a subject: i) prevents the inception or recurrence orii) causes the reduction or remission of the disease or conditionagainst which the compound, composition or formulation is effective.

The term “thioureylene” as used herein, relates to a group of compoundsof general formula R₁—CS—NR₂R₃, wherein R₁, R₂ and R₃ are organicradicals, used in the treatment of hyperthyroiditis. Examples ofthioureylene compounds include, but are not limited to, carbimazole,methimazole, methylthiouracil and propylthiouracil.

The term “treat” or “treatment” as used herein, refers to theadministration of a composition or formulation of the invention to asubject in order to control the progression of a disease after itsclinical signs have shown. Control of the disease progression isunderstood to mean the beneficial or desired clinical results thatinclude, but are not limited to, reduction of the symptoms, reduction ofthe duration of the disease, stabilization of pathological states(specifically to avoid additional deterioration), delaying theprogression of the disease, improving the pathological state, andremission (both partial and total). The control of progression of thedisease also involves an extension of survival, compared with theexpected survival if treatment is not applied.

2. Liquid Compositions

In a first aspect, the present invention relates to a compositioncomprising a thioureylene compound, a pharmaceutically acceptable salt,solvate, prodrug or combination thereof, a polysaccharide and a liquidvehicle. Preferably, the thioureylene compound is selected from thegroup consisting of carbimazole, methimazole, methylthiouracil,propylthiouracil, their pharmaceutically acceptable salts, solvates,prodrugs and combinations thereof. More preferably, the thioureylenecompound is carbimazole, methimazole, their pharmaceutically acceptablesalts, solvates, prodrugs or combinations thereof. Further preferably,the thioureylene compound is methimazole, its pharmaceuticallyacceptable salts, solvates, prodrugs or combinations thereof. In oneembodiment, the composition comprises about 0.25% to about 1% w/v of thethioureylene compound, its pharmaceutically acceptable salts, solvates,prodrugs or combinations thereof.

In one embodiment, the polysaccharide of the composition of theinvention is selected from the group consisting of amphoteric (e.g.carboxymethylchitosan, N-hydroxy-dicarboxyethyl-chitosan, modifiedpotato starch), anionic (e.g. alginic acid, pectin, xanthan gum,hyaluronic acid, chondroitin sulfate, gum arabic, gum karaya, gumtragacanth, carboxymethyl-chitin, cellulose gum), cationic (e.g.chitosan, cationic guar gum, cationic hydroxyethylcellulose (HEC)),hydrophobic (e.g. cetyl hydroxyethylcellulose, poly-quaternium 24) andnon-ionic (e.g. starch, dextrins, guar gum, cellulose ethers (such ashydroxyethylcellulose, methylcellulose or nitrocellulose))polysaccharides and the combinations thereof. Preferably, thepolysaccharide is anionic. More preferably, the anionic polysaccharideis a gum, such as xanthan gum. Examples of suitable xanthan gums thatcan be used in the composition of the invention include RHODIGEL® (e.g.23, 80), KELTROL® (e.g. F, T, TF, 1000) and MEREZAN®. Preferably, amixture of RHODIGEL® 23 and 80 is employed.

Preferably, the composition comprises at least about 0.2% w/v of thepolysaccharide. More preferably, the composition comprises at leastabout 0.4% w/v of the polysaccharide.

The liquid vehicle according to the invention is selected from the groupconsisting of a hydrophobic oily carrier and water. Preferably, thehydrophobic oily carrier comprises: i) a vegetable oil, ii) one or moretriglycerides of medium chain fatty acids or iii) a combination of i)and ii). Examples of vegetable oils include, but are not limited to,almond oil, cottonseed oil, olive oil, peanut oil, safflower oil, sesameoil, soybean oil, or a combination thereof. Medium chain fatty acids areC₆-C₁₈ fatty acids. Preferably, the fatty acids are saturated. Morepreferably, the triglyceride is selected from the group consisting ofcapric triglyceride, caprylic triglyceride and combinations thereof. Theliquid vehicle is present in about 40% to 98% w/v, preferably in about60 to 98% w/v, and more preferably in about 78% to about 98% w/v, of thetotal composition volume, depending on the nature and the amount ofother excipients present in the liquid composition.

In an additional embodiment, the composition according to the inventionfurther comprises a thickening agent. Said thickening agent includes,but is not limited to, acetylated distarch adipate, acetylated distarchphosphate, acetylated oxidized starch, acetylated starch, acid treatedstarch, agar, alginic acid, alkaline treated starch, aluminumdistearate, ammonium alginate, arabinogalactan, bleached starch, calciumalginate, carrageenan, dextrin roasted starch, distarch phosphate,enzyme treated starch, gellan gum, guar gum, gum arabic, glycerol,hydrogenated castor oil, hydroxypropyl cellulose, hydroxypropyl distarchphosphate, hydroxypropyl methylcellulose, hydroxypropyl starch, karayagum, konjac gum, locust bean gum, methyl ethyl cellulose,methylcellulose, monostarch phosphate, oxidized starch, pectin,phosphated distarch phosphate, potassium alginate, processed eucheumaseaweed, propane-1,2-diol alginate, polyvinylpyrrolidone, odiumalginate, starch sodium octenylsuccinate, tara gum, tragacanth, triethylcitrate or a combination thereof.

In one version of this embodiment, the thickening agent is suitable foruse with water. Preferably, glycerol, polyvinylpyrrolidone or acombination thereof is used as thickening agent when water is employedas liquid vehicle.

Preferred realizations of the composition of the invention when thevehicle is water include, but are not limited, to the followingcombinations of active agent, xanthan gum and thickening agent(s):carbimazole and xanthan gum; methimazole and xanthan gum;methylthiouracil and xanthan gum; propylthiouracil and xanthan gum;carbimazole, xanthan gum and glycerol; methimazole, xanthan gum andglycerol; methylthiouracil, xanthan gum and glycerol; propylthiouracil,xanthan gum and glycerol; carbimazole, xanthan gum andpolyvinylpyrrolidone; methimazole, xanthan gum and polyvinylpyrrolidone;methylthiouracil, xanthan gum and polyvinylpyrrolidone;propylthiouracil, xanthan gum and polyvinylpyrrolidone; carbimazole,xanthan gum, glycerol and polyvinylpyrrolidone; methimazole, xanthangum, glycerol and polyvinylpyrrolidone; methylthiouracil, xanthan gum,glycerol and polyvinylpyrrolidone; and propylthiouracil, xanthan gum,glycerol and polyvinylpyrrolidone.

In another version of the previous embodiment, the thickening agent issuitable for use with a hydrophobic oily carrier. Preferably, aluminumdistearate, hydrogenated castor oil or a combination thereof is used asthickening agent in this case.

Preferred realizations of the composition of the invention when thevehicle is a mixture of capric and caprylic triglycerides include, butare not limited, to the following combinations of active agent, xanthangum and thickening agent(s): carbimazole and xanthan gum; methimazoleand xanthan gum; methylthiouracil and xanthan gum; propylthiouracil andxanthan gum; carbimazole, xanthan gum and aluminum distearate;methimazole, xanthan gum and aluminum distearate; methylthiouracil,xanthan gum and aluminum distearate; propylthiouracil, xanthan gum andaluminum distearate; carbimazole, xanthan gum and hydrogenated castoroil; methimazole, xanthan gum and hydrogenated castor oil;methylthiouracil, xanthan gum and hydrogenated castor oil;propylthiouracil, xanthan gum and hydrogenated castor oil; carbimazole,xanthan gum, aluminum distearate and hydrogenated castor oil;methimazole, xanthan gum, aluminum distearate and hydrogenated castoroil; methylthiouracil, xanthan gum, aluminum distearate and hydrogenatedcastor oil; and propylthiouracil, xanthan gum, aluminum distearate andhydrogenated castor oil.

Preferably, the composition comprises at least about 0.5% w/v of thethickening agent. More preferably, the composition comprises about 1.0%w/v to about 20% w/v of the thickening agent.

In a further embodiment, the composition according to the inventioncomprises a wetting agent. Examples of wetting agents according to theinvention include, but are not limited to, beta-cyclodextrin, brominatedvegetable oil, calcium stearoyl lactylate, choline salts and esters,cross-linked sodium carboxymethylcellulose, dioctyl sodiumsulfosuccinate, magnesium stearate, polyglycerol polyricinoleate,polyoxyethylene stearate, polysorbate (i.e. 20, 40, 60, 65, 80),simethicone emulsion, sodium carboxymethylcellulose, sodium stearoyllactylate, sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan tristearate, stearyltartarate, sucroglycerides, sucrose acetate isobutyrate,superglycerinated hydrogenated rapeseed oil, oxidized soya bean oil or acombination thereof. Preferably, simethicone emulsion is applied aswetting agent when a water-based liquid vehicle is employed. When ahydrophobic oily vehicle is used instead, polysorbate 80 is preferred aswetting agent. Preferably, the composition comprises about 0.1% to about1.0% w/v of the wetting agent.

In an additional embodiment, the composition comprises a pH buffersolution. Preferably, the pH buffer solution is selected from the groupconsisting of citric acid, disodium phosphate dihydrate, sodiumdihydrogen phosphate dihydrate and combinations thereof. Morepreferably, the pH buffer solution is utilized when a water liquidvehicle is employed. Preferably, the pH of the liquid composition is ofabout 3.0 to about 7.0, and more preferably of about 4.3 to 6.0, at 25°C. as measured according to Ph. Eur. 2.2.3.

In another embodiment, the composition further comprises a preservative.Examples of preservatives include, but are not limited to, benzoic acid,diphenyl (biphenyl), borax, boric acid, calcium benzoate, calciumdisodium EDTA, calcium formate, calcium propionate, calcium sorbate,dehydroacetic acid, dimethyl dicarbonate, ethyl para-hydroxybenzoate,examethylene tetramine (hexamine), formaldehyde, formic acid, gumguaicum, heptyl p-hydroxybenzoate, lecithin citrate, lysozyme,methylparaben (methyl para-hydroxybenzoate), natamycin (pimaricin),nisin, orthophenyl phenol (2-hydroxybiphenyl), phytic acid, potassiumbenzoate, potassium propionate, potassium sorbate, propionic acid,propylparaben (propyl para-hydroxybenzoate), sodium benzoate, sodiumdehydroacetate, sodium ethyl para-hydroxybenzoate, sodium formate,sodium methyl para-hydroxybenzoate, sodium orthophenyl phenol, sodiumpropionate, sodium propyl para-hydroxybenzoate, sodium sorbate, sodiumtetraborate and thiabendazole. Preferably, the preservative is sodiumbenzoate. The preservative is applied, preferably, when a water-basedliquid vehicle is used.

In a further embodiment, the liquid compositions of the inventioncomprise optionally a coloring (e.g. food yellow no. 5, food red no. 3,food blue no. 2, food lake dye, titanium dioxide, red iron oxide, yellowiron oxide) or flavoring (e.g. honey, caramel, carrot, apple, cinnamonoil) agent. The liquid compositions of the invention may also includeadditional ingredients commonly used in the preparation of human andveterinary products. For example, sweeteners (e.g. sugar, saccharin),antioxidants (e.g. BHT, BHA) and dispersants (e.g. calcium stearate) canbe added to the compositions.

In yet another embodiment, the liquid compositions of the inventionconsist essentially of:

-   -   i) about 0.25% to about 1% w/v of a thioureylene compound, a        pharmaceutically acceptable salt, solvate, prodrug or        combination thereof,    -   ii) at least about 0.2% w/v of polysaccharide, and    -   iii) a liquid vehicle.

In another embodiment, the liquid compositions of the invention consistessentially of:

-   -   i) about 0.25% to about 1% w/v of a thioureylene compound, a        pharmaceutically acceptable salt, solvate, prodrug or        combination thereof,    -   ii) at least about 0.2% w/v of polysaccharide    -   iii) at least about 0.5% w/v of a thickening agent, and    -   iv) a liquid vehicle.

3. Process of Making Liquid Compositions

In another aspect, the present invention is directed to a process ofpreparing the liquid composition of the invention, which comprisesmixing: 1) a thioureylene compound, a pharmaceutically acceptable salt,solvate or prodrug thereof, 2) a polysaccharide and 3) a liquid vehicle.Preferably, about 0.25% to about 1% w/v of the thioureylene compound, apharmaceutically acceptable salt, solvate, prodrug or combinationthereof, at least about 0.2% w/v of the polysaccharide and the liquidvehicle are mixed according to the process of the invention. In anadditional version of this aspect, the process of making the liquidcomposition of the invention further comprises mixing it with athickening or wetting agent.

4. Pharmaceutical Formulations

In another aspect, the present invention relates to a pharmaceuticalformulation comprising the liquid composition of the invention and atleast one excipient. Preferably, the pharmaceutical formulation issuitable for oral administration such as an oral solution, oralsuspension, feed premix, gels, capsule or bolus. The formulations of theinvention may be produced following methods known in the art. See GunnarA, Ed., “Remington: The Science and Practice of Pharmacy” 20th ed.(Lippincott Williams & Wilkins, Philadelphia, Pa., US, 2003).

Examples of excipients which may be used for preparing thepharmaceutical formulations of the invention include, but are notlimited to, solid powdery vehicles with low water content, sugaralcohols (e.g. mannitol, xylitol, sorbitol), sugars (e.g. lactose,fructose, glucose, sucrose, saccharose), cellulose and cellulosederivatives (e.g. microcrystalline cellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose), mixtures and compounds, respectively,from cellulose derivatives with other excipients (e.g. silicone dioxide,guar gum, carboxymethylcellulose sodium), natural or modified starches(e.g. corn starch, potato starch), silicone dioxide and silicates (e.g.magnesium, aluminum and calcium silicate) and phosphates (e.g. calciumand magnesium phosphate), or a combination thereof.

Other suitable excipients for the stabilization of formulations include,in particular, buffers with a pH value of about 4.3 or higher, such asbuffer solutions comprising citric acid, disodium phosphate dihydrate,sodium carbonate, sodium dihydrogen phosphate, sodium hydrogencarbonate, sodium hydroxide or combinations thereof.

5. Use of Liquid Compositions or Formulations for Lowering ThyroidHormone Levels

In another aspect, the present invention refers to the use of a liquidcomposition according to the invention and a pharmaceutical formulationcontaining said liquid composition for lowering thyroid hormone levels.In a particular embodiment, the liquid compositions and pharmaceuticalformulations of the invention are useful for lowering the plasmaticlevels of the T₃ and T₄ thyroid hormones. In a further version of thisembodiment, the compositions and pharmaceutical formulations of theinvention are used for treating or preventing hyperthyroidism.Preferably, the compositions and pharmaceutical formulations of theinvention are used for treating hyperthyroidism.

Preferably, the liquid compositions or formulations of the invention areadministered periodically, such as on a daily basis. The dosage regimenmay vary according to the clinical protocols that are applicable to thesubject under treatment and that are known in the art.

According to the invention, the liquid compositions can be administeredby any formulation adequate for oral delivery. Suitable oralformulations include oral solutions, oral suspensions, feed premix,gels, capsules or boluses. Preferably, the liquid compositions of theinvention are administered as oral pharmaceutical formulations.

This invention is further illustrated by the following examples whichshould not be construed as limiting. The contents of all documents citedthroughout this application are incorporated herein in their entirety byreference.

General Procedures

1. Process for Making Water-Based Liquid Compositions

A. Pre-Mix

First, sodium benzoate is dissolved in 150 liters of purified water at20-25° C. using a silverson mixer at low speed (2500 rpm). Second,polyvinylpyrrolidone K30 (FLUKA®81420, Sigma-Aldrich Company Ltd.,Dorset, GB) is added to the solution and is mixed at low speed (2500rpm). Third, xanthan gum (RHODIGEL® 80/23, Rhodia Chimie,Boulogne-Billancourt, FR) is added slowly to the blend and is mixed atlow speed (2500 rpm) for 30 min or until completely dispersed. Finally,glycerol is added to the combination and is mixed at 2500 rpm for 10 minto obtain a pre-mix.

B. Active Ingredient Solution

Disodium phosphate dehydrate, sodium dihydrogen phosphate, citric acid,a thioureylene compound (e.g. carbimazole, methimazole,methylthiouracil, propylthiouracil, its pharmaceutically acceptablesalt, solvate or prodrug thereof) and simethicone emulsion (DOW CORNING®Q7-2587, Dow Corning Corp., Midland, Mich., US) are added one by 20 oneto 16 liters of purified water at 20-25° C. and are mixed at 2500 rpmusing a silverson mixer for 10 min or until completely dissolved toobtain an active ingredient solution.

C. Liquid Composition

The pre-mix and the active ingredient solution are mixed at 2500 rpm for15 min or until completely dispersed. Subsequently, a flavor agent isincorporated to the solution and is mixed with a silverson mixer at 2500rpm for 5 min or until dispersed. Purified water at 20-25° C. is pouredin to complete 200 liters of solution and is mixed at 2500 rpm for 10min or until completely dispersed.

2. Process for Making Oil-Based Liquid Compositions

Polysorbate 80, aluminum distearate, hydrogenated castor oil and athioureylene compound (e.g. carbimazole, methimazole, methylthiouracil,propylthiouracil, its 35 pharmaceutically acceptable salt, solvate orprodrug thereof) are added one by one to 16 liters of a caprylic/caprictriglyceride liquid vehicle (MIGLYOL 8100®, Dynamit Nobel 5 GmbH,Leverkusen, Del.) and are mixed at 2500 RPM using a silverson mixer for10 min or until completely dissolved. The caprylic/capric triglyceridemixture is poured in to complete 200 liters of solution and is mixed at2500 rpm for 10 min or until completely dispersed.

Example 1 Water-Based Liquid Compositions

Water-based liquid compositions having the ingredients and content inweight by volume percentage of Table 1 were prepared according to theprotocols above.

TABLE 1 Ingredient O-MET-010 O-MET-030 O-MET-040 Methimazole 0.5% 0.5% 0.5% Sodium benzoate 0.15%  0.15%  0.15% Glycerol  15%  15%  15%Polyvinylpyrrolidone  1%  1%   1% K30 Xanthan gum 0.4% 0.2% — Disodiumphosphate 0.25%  0.25%  0.25% dehydrate Sodium dihydrogen 1.02%  1.02% 1.02% phosphate Citric acid 0.325%  0.325%  0.325%  Honey flavor 0.2%0.2%  0.2% Simethicone emulsion 0.2% 0.2% — Purified water 81.95% 82.15%  82.55% 

Aliquots of the O-MET-010 solution were stored at: i) 25° C. and 60%relative humidity (“Rif”), ii) 30° C. and 65% RH and iii) 40° C. and 75%RH. The stability of the aliquots was assayed after 1 year of storage.All aliquots were found to be stable.

Compositions containing 0% and 0.2% w/v (i.e. O-MET-040, O-MET-030)instead of 0.4% w/v xanthan gum (i.e. O-MET-010) were prepared accordingto the protocols above. The compositions were stored at 40° C. and 75%RH for 1 year. After this period, the stability of the compositions wasassayed. The O-MET-030 and O-MET-040 solutions were found to beunstable.

Example 2 Oil-Based Liquid Compositions

An oil-based liquid composition having the ingredients and content inweight by volume percentage of Table 2 was prepared according to theprotocols above.

TABLE 2 Ingredient O-MET-020 Methimazole 0.5% Polysorbate 80 0.5%Aluminum distearate 0.5% Hydrogenated castor oil 0.5% Caprylic/caprictriglycerides 98.0%

Aliquots of the O-MET-020 solution were stored at: i) 25° C. and 60% RH,ii) 30° C. and 65% RH and iii) 40° C. and 75% RH. The stability of thealiquots was assayed after 1 year of storage. All aliquots were found tobe stable.

Example 3 Pharmacokinetic Comparison of the O-MET-010 Solution and theFelimazole® 5 mg Coated Tablets

A pharmacokinetic study in cats following the oral administration of theO-MET-010 solution and FELIMAZOLE® 5 mg coated tablets for cats (UKmarketing authorization: Vm 10434/4061; Dechra Veterinary Products Ltd.,Nortwich, GB) was conducted to determine the plasma levels ofmethimazole. The pharmacokinetic parameters AUC_(t) (area under theconcentration/time curve), C_(max) (the maximum concentration) andT_(max) (time of maximum concentration) were determined.

Eighteen cats, weighing between 4-8 kg and aged between 1-8 years, wereassigned to 2 treatment groups (i.e. A, B) each consisting of 9 animals.The animals were allocated in such a way as to eliminate any weightbias. The study was conducted following a staggered, two-treatment,two-period crossover protocol.

The A and B group subjects were administered the O-MET-010 solution andthe Vm 10434/4061 tablets, respectively, once (period I). Then, theadministration was interrupted for 30 days (washout period), and wasresumed afterwards inverting the test products: the A group subjectsreceived the Vm 10434/4061 tablets, and the B group subjects receivedthe O-MET-010 solution once (period II). The O-MET-010 solution and theVm 10434/4061 tablets were administered at an equivalent dose of 5 mgmethimazole per animal.

Blood samples were taken by jugular catherization or venipuncture fromthe jugular or cephalic veins using a syringe. Immediately aftercollection, the samples were transferred to heparinized containers andplaced on ice, prior to centrifuging and removal of the plasma. Thesamples were then assayed by HPLC for methimazole concentration. Table 3shows the mean and standard deviation values of several pharmacokineticparameters relating to the methimazole plasma levels after the oraladministration of the O-MET-010 solution and Vm 10434/4061 tablet at adose rate of 5 mg methimazole per subject. See FIG. 1.

TABLE 3 O-MET-010 Vm 10434/4061 Ratio means PK parameters solution (A)tablet (B) (A)/(B) Cmax (ppm) 1.13 ± 0.27 1.19 ± 0.25 94.96% Tmax(hours) 1.14 ± 1.04 1.02 ± 0.62 111.76% AUC (ppm hours) 5.85 ± 0.95 6.26± 1.25 93.45% AUMC (ppm hours{circumflex over ( )}2) 23.30 ± 4.29  27.92± 12.32 83.45% MRT (hours) 3.96 ± 0.37 4.38 ± 1.12 90.41% T ½ (hours)4.35 ± 0.64 4.85 ± 1.18 89.69%

The results above demonstrate that the O-MET-010 solution and the Vm10434/4061 tablet formulations are bioequivalent according to theapplicable USFDA regulations. Seehttp://www.fda.gov/drugs/developmentapprovalprocess/ucm79068.htm, June2014.

Example 4 Stability of the Liquid Compositions

Water-based liquid compositions having the ingredients and content inweight by volume percentage of the O-MET-010 solution of Table 1 wereprepared according to the protocols above. Aliquots of the compositionswere stored at: i) 25° C. and 60% RH, ii) 30° C. and 65% RH and iii) 40°C. and 75% RH. The stability of the aliquots was assayed after 1 year ofstorage. All the O-MET-010 liquid solutions were found to be stable. SeeTable 4.

TABLE 4 Methimazole pH Time Temp RH (w/v %) @ 25° C. Stability 0 — —0.524 4.45 100% 12 months 25° C. 60% 0.537 4.43 100% 12 months 30° C.65% 0.537 4.46 100% 12 months 40° C. 75% 0.526 4.38 100%

The invention claimed is:
 1. An oral liquid composition comprising: i)from about 0.25% to about 1% w/v of methimazole, a pharmaceuticallyacceptable salt thereof, a solvate thereof, or a prodrug thereof, ii) athickening agent, which is glycerol, and iii) a liquid vehicle.
 2. Thecomposition of claim 1, wherein the liquid vehicle is selected from thegroup consisting of a hydrophobic oily carrier and water.
 3. Thecomposition according to claim 2, wherein the hydrophobic oily carriercomprises a triglyceride of C₆-C₁₈ chain fatty acid.
 4. The compositionaccording to claim 3, wherein the triglyceride is selected from thegroup consisting of capric triglyceride, caprylic triglyceride andcombinations thereof.
 5. The composition according to claim 1, whereinthe thickening agent is at least about 0.5% w/v of the total compositionvolume.
 6. The composition according to claim 1, further comprising awetting agent.
 7. The composition according to claim 6, wherein thewetting agent is 0.1% to about 1.0% w/v of the total composition volume.8. The composition according to claim 6, wherein the wetting agent isselected from the group consisting of polysorbate 80, simethiconeemulsion and combinations thereof.
 9. The composition according to claim1, further comprising a pH buffer solution.
 10. The compositionaccording to claim 9, wherein the pH buffer solution is selected fromthe group consisting of citric acid, disodium phosphate dihydrate,sodium dihydrogen phosphate dihydrate and combinations thereof.
 11. Thecomposition according to claim 9, wherein the pH of the composition isat least about 4.3 or more.
 12. The composition according to claim 1,further comprising a preservative.
 13. The composition according toclaim 1, wherein the preservative comprises sodium benzoate.
 14. Thecomposition according to claim 1, further comprising a sweetener. 15.The composition according to claim 1 further comprising a sugar alcohol.16. The composition according to claim 15, wherein the sugar alcohol isselected from mannitol, xylitol and sorbitol.